Cytochrome c oxidase (COX) deficiency leads to several mitochondrial encephalomyopathies (MEMs). Since many of these are genetic disorders, a genetically tractable animal model can help in understanding them and in developing therapeutic strategies against them. An animal model has been established to explore therapeutic approaches towards COX-deficiency related MEMs. Mutations have been generated in a gene (designated levy) in Drosophila, a genetically sophisticated animal model system. The levy mutants recapitulate symptoms of Leigh syndrome (LS), a COX-deficiency induced MEM, in humans. Clinical features of LS include loss of motor skills, clumsiness, seizures, partial paralysis and progressive neurodegeneration. LS appears at a very young age, generally within the first few months of life, and the patient dies at an early age. In addition to generating the levy mutations, a mutation has been generated in a second gene, Su(levy), that suppresses the effects of the levy mutations. The proposed project is aimed at identifying the Su(levy) gene product and analyzing the role of this gene product in normal physiological function. This would provide clues to developing pharmacological approaches to suppress COX-deficiency induced MEMs. For example, the product encoded by the Su(levy) gene could be an enzyme, a transporter, a receptor, or some other component. Since the mutational disruption of the Su(levy) gene product suppresses levy induced MEM, pharmacological inhibitor of the gene product could be explored for carrying out a similar suppression of COX-deficiency mediated MEMs. Thus the availability of the levy mutations, and particularly of the Su(levy) mutation, provides a unique opportunity to explore therapeutic approaches towards these disorders. Specifically, the Aims are to (i) identify the Su(levy) gene and the product that it codes for, and (ii) study the role of Su(levy) gene product in normal cellular physiology. These studies will help us understand molecular mechanisms underlying MEMs in general, and COX-deficiency mediated MEMs in particular, and provide leads towards genetic and pharmacological treatments against these disorders. PUBLIC HEALTH RELEVANCE: Cytochrome c oxidase (COX) deficiency leads to several mitochondrial encephalomyopathies (MEMs), for which no treatment is available. The proposed studies would provide leads on the mechanisms underlying these disorders and on possible therapeutic approaches to treat them.